We have recently demonstrated that one of the active components of marihuana, delta 9-Tetrahydrocannabinol, (delta 9-THC) possesses anti- neoplastic activity in two solid small growth fraction murine tumors and one virus induced tumor. In in vivo experiments delta 9-THC inhibits the incorporation of H3 thymidine into tumor DNA and in in vitro cell suspension and tissue culture inhibits incorporation of H3 thymidine and H3 uridine into the acid precipitable cell fraction. Additionally, we have shown at least a 10 fold increase in delta 9-THC's sensitivity to Lewis lung carcinoma cell over bone marrow cells as measured by inhibition of H3 thymidine uptake and trypan blue exclusion. It is the overall goal of this project to determine if one or more cannabinoids possess sufficient anti-cancer activity and acceptable side effects to warrant clinical treatment. To meet this goal we will work toward the following objectives: 1) determine optimum dosage, time schedule, and route of administration of delta 9-THC; 2) test delta 9-THC, using above experimental design, for anti-tumor activity against the B16 melanoma and anti-tumor virus activity against Friend leukemia; 3) synthesize and test new cannabinoids analogs for anti-cancer activity in order to optimize the therapeutic index; 4) determine the site and nature (mechanism) of tolerance to delta 9-THC's anti-neoplastic actions and 5) design and test combinations of cannabinoids, immunopotentiators and known cytostatic drugs for synergistic anti-neoplastic activity using the Lewis lung carcinoma. The use of a small growth fraction solid tumor for these investigation more closely represents the majority of human cancers. Cannabinoids are known to enter the central nervous system (CNS), an activity not common among most anti-cancer drugs. The limiting adverse reactions of the cannabinoid are dissimilar to presently used anti-cancer drugs in that they produce behavioral alterations with minimal deleterious activity of rapidly dividing tissues. However, there are many known cannabinoids without CNS activity whcih may possess anti-neoplastic activity.